4-Oxo-2-imidazolidinylidene ureas

ABSTRACT

Compounds of the class of 4-oxo-2-imidazolidinylidene ureas and 4-oxo-2-hexahydropyrimidinylidene ureas, useful as anti-secretory agents and central nervous system (CNS) depressants.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part of my co-pending applicationSer. No. 508,795, filed Sept. 23, 1974, now abandoned which in turn is aContinuation-in-Part of my application Ser. No. 408,022, filed Oct. 19,1973, now abandoned.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel 4-oxo-2-imidazolidinylidene ureas and4-oxo-2-hexahydropyrimidinylidene ureas of this invention may bestructurally represented by the formulas: ##SPC1##

Wherein R₁ is a member selected from the group consisting of hydrogenand loweralkyl, preferably hydrogen; R₂ is a member selected from thegroup consisting of hydrogen and loweralkyl, preferably methyl; R₃ is amember selected from the group consisting of hydrogen and aryl,preferably hydrogen; R₄ is a member selected from the group consistingof hydrogen, aryl, and arylalkyl, preferably hydrogen; and Ar is aryl;provided that said R₃ and said R₄ are other than 2,6-disubstituted aryl.This restriction on the identity of R₃ and R₄ is imposed because thesteric hindrance occurring if R₃ and R₄ are not so restricted makespreparation of such compounds difficult.

As used herein, "loweralkyl" and "loweralkoxy" may be straight or branchchained and have from 1 to about 8 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, and the likealkyls, and respectively, the corresponding alkoxys such as methoxy,ethoxy, etc. The term "halo" is generic to fluoro, bromo, chloro andiodo.

The term "aryl" includes phenyl, nitrophenyl, trifluoromethylphenyl,diloweralkyaminophenyl, and phenyl substituted with one to three memberseach selected from the group consisting of halo; loweralkyl, andloweralkoxy. The term "arylalkyl" means benzyl, phenethyl, phenpropyl,and the like arylalkyls, but the preferred arylalkyl is benzyl.

The compounds of formula (I) wherein either R₁ or R₂ (or both) arehydrogen may exist in several tautomeric forms besides that representedby formula (I). These forms are represented by the following: ##SPC2##

Wherein R₁, R₂, R₃, R₄ and Ar are as previously defined. The compoundsof formula (I') may likewise exist in two similar tautomeric forms.

The 4-oxo2-imidazolidinylidene ureas of formula (I) are readily obtainedby the reaction of an appropriate 2-imino-imidazolidin-4-one (II) withan appropriate aryl isocyanate (III). A slight stoichiometric excess ofthe former reactant is preferred to ensure complete reaction with thearyl isocyanate. The reaction is preferably conducted in an anhydrous,polar, inert, aprotic, organic solvent such as, for example, apolyethereal solvent, e.g., dioxane, tetrahydrofuran (THF),1,2-dimethoxy-ethane, the dimethyl ether of diethylene glycol, and thelike; N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO);hexamethylphosphoric acid triamide; and other similar organic solvents.Any excess 2-imino-1-R-imidazolidin-4-one reactant (II) is filtered offafter the reaction is completed and the desired product is generallyrecovered by the addition of cold water to the reaction mixture. Thecrude precipitated product may then be purified by standardrecrystallization techniques from suitable organic solvents. In caseswhere the purified product is obtained in large crystalline form, it maybe pharmaceutically advantageous to reduce the size of the crystals bystandard techniques known in the art, i.e., milling, micronization,reprecipitation, etc. These techniques are known to result in enhancedabsorption and bioavailability of a given medicament. ##SPC3##

In a completely analogous manner, the 4-oxo-2-hexahydropyrimidinylideneureas of formula (I') may be obtained by the reaction of an2-imino-1-methyl-hexahydropyrimidin-4-one (II') with an appropriate arylisocyanate (III). This reaction is illustrated by the following:##SPC4##

The subject compounds of formulas (I) and (I') have been found topossess useful anti-secretory activity by the following acute gastricfistula rat test. The anti-secretory activity of the compound to betested is studied in female Sprague-Dawley rats after intraduodenal(i.d.) injection of the compound at doses generally ranging from 2.5-40mg/kg body weight. The rats are fasted 24 hours before testing and aregiven water ad libidum while being kept in individual cages. On the dayof testing, the rats are weighed and are selected so that the rats ineach test have weights within a range of +20 g.

Surgery is carried out under light ether anesthesia. As soon as the ratis anesthetized, its teeth are removed, using a small pinch pliers. Amid-line incision is made on the abdoment about 11/2 cm in length andthe stomach and duodenum are exposed. If at this point the stomach isfilled with food or fecal material, the rat is discarded. Using 4-0MERSILENE Suture, a purse string stitch is placed on the fundic portionof the stomach taking care not to pierce any blood vessels in the area.A small nick is made into the stomach in the center of the purse string,and a cannula, consisting of a small vinyl tube with a flange on oneend, is put into the stomach and the purse string stitch is closedtightly around the flange. Immediately following this, the test compoundis administered I.D. in a volume of 0.5 ml per 100 gm rat. Three ratsare generally used for each drug dose tested. Control rats receive thetest vehicle, usually 0.5% aqueous methyl cellulose.

After administration of the test compound, the abdominal wall and skinare closed simultaneously with 3 or 4 18 mm wound clips and a collectingtube is placed on the cannula. Each rat is then placed in a box in whicha longitudinal slit has been made to allow the cannula to hang freelyand to allow the rat to move about unencumbered. After the rat isallowed to stabilize for 30 minutes, the collection tube on the cannulais discarded and replaced with a clean tube to receive the gastricjuice. Collections are made at one hour. At the end of the study, thecannula is removed and the rat is sacrificed.

The sample of gastric contents collected is drained into a centrifugetube and centrifuged to pack down the sediment. Volumes are read and a 1ml aliquot of the supernatant is put into a beaker containing 10 mldistilled H₂ O and is titrated to pH7 using 0.01N NaOH. Results aredetermined for Volume, Titratable Acid, and Total Acid Output whereVolume = total ml. of gastric juice minus sediment; Titratable Acid(milliequivalents/1) = amount of 0.01N NaOH needed to titrate the acidto pH7; and Total Acid output = Titratable Acid × Volume. Results arereported in % Inhibition vs Controls.

The vast majority of the compounds of the invention exhibit usefulanti-secretory activity as measured by the above test, particularlythose compounds of formulas (I) and (I') wherein Ar is other thantrisubstituted phenyl.

In addition, the subject compounds of formulas (I) and (I') have beenfound to possess useful CNS depressant properties as demonstrated in oneor more of the following tests indicative of such activities onlaboratory animals.

Test A:

An anti-anxiety assay as reported by I. Geiler in PsychosomaticMedicine, eds. J. H. Nadine and J. H. Moyer (Lea and Febiger, Phila.) p.267 (1962) and modified by D. L. Margules and L. Stein inPsychopharmacologia (Berl.) 13, 74-80 (1968). The anti-anxiety activityof the compound to be tested is studied in rats daily for 5 days afterintraperitoneal (i.p.) injection of the compound at doses generallyranging from 5-25 mg/kg body weight and the effect of the compound isobserved on the animal's bar pressing rate while working for foodreinforcement. Activity is also observed after oral administration ofdoses generally ranging from 5-25 mg./kg. body weight by the identicalprocedure. The method consists of determining the effect of a testcompound on non-punished and punished responses. Hungry rats are trainedto press a bar for food reinforcement: a dipper full of milk isdelivered to the rat on the average of once every two minutes (variableinterval schedule - V.I. II). Following 12 minutes on this schedule, atone is presented for three minutes which signals the rewarding andsimultaneous punishment of each bar press (a dipper full of milk ispresented and accompanied by a shock, delivered through the grid floor,with each bar press). The shock delivered is 0.2 milli-seconds induration and ranges in intensity from 0.5 to 3.5 milli-amperes. Each ratis presented with 4 to 6 alternating pairs of unpunished periods whenmilk alone is given and punished periods when milk and shock areadministered. Control responses are obtained for each rat after salineintraperitoneal injection daily for 5 days. Each rat is evaluated at thesame time of day and in the same test chamber. Responses are recordedand reinforcements (milk) and punishment (shock) delivered by means ofsuitable automated equipment. The activity of the compound to be testedis evaluated by comparing the number of bar presses after placeboadministration with the number after administration of the compound ineach rat.

Test B:

A muscle-relaxant assay as judged by the effect of the compound to betested on strychnine-induced seizures as described by M. J. Orloff etal., Proc. Soc. Exp. Biol. and Med. 70, 254 (1949) as modified by G.Chen and B. Bohner, J. Pharmacol. and Expt. Therap. 117, 142 (1956). Theanti-strychnine activity is observed in mice at oral doses of about25-500 mg./kg. body weight by determining the effect of the compound onthe seizure threshold induced by strychnine.

Test C:

A mouse behavioral assay as described by S. Irwin, Gordon ResearchConference on Medicinal Chemistry, 1959, p. 133. In this assay, suchsymptoms as ataxia, decrease in motor activity and loss of rightingreflex are observed after intraperitoneal (i.p.) administration in miceof the compound to be treated at doses ranging from 10-300 mg./kg. bodyweight.

In view of the foregoing, an effective CNS depressant amount of acompound of formula (I) or (I') intimately admixed with apharmaceutically acceptable carrier may be systemically administered towarm-blooded animals, including humans, to elicit a CNS depressantresponse. When administering the hereinabove described dosage unit formsfor such purpose, amounts of active ingredient ranging about 15-500 mg,and preferably about 15-250 mg, per dosage unit may be utilized.

Among the preferred compounds of the invention are those of formula (I)wherein R₁ R₃ R₄ hydrogen, R₂ is methyl, and Ar is ##SPC5##

wherein X is a member selected from the group consisting of hydrogen,halo, methyl, ethyl, methoxy, ethoxy, and trifluoromethyl. The mostpreferred compounds of formula (I) are those wherein R₁ = R₃ = R₄ =hydrogen, R₂ is methyl, and Ar is ##SPC6##

wherein X is a member selected from the group consisting of hydrogen,methyl, methoxy, chloro, bromo, and trifluoromethyl. These preferredcompounds are especially useful for their anti-anxiety activity.

Accordingly, this invention provides a process of alleviating anxietywhich comprises systemically administering to an anxious individual, forexample, one whose anxiety inhibits his ability to cope with the variousrequirements of his daily life, or one whose anxiety would have anadverse effect on his physical well-being, an aforementioned compound asthe active ingredient in a concentration adequate to elicit an effectiveanti-anxiety response. Preferably, dosage unit forms containing fromabout 15 to about 500 mg of such active ingredient are employed foranti-anxiety purposes. A suitable human regimen contemplated for themost preferred compounds disclosed above is 15 to 500 mg orally orparenterally administered three or four times a day.

For purposes of relaxing skeletal muscle, the preferred compounds offormula (I) are those wherein R₁ = R₃ = R₄ = hydrogen, R₂ is methyl andAr is a member selected from the group consisting of ##SPC7##

wherein A is a member selected from the group consisting of halo andloweralkyl; B is a member selected from the group consisting of halo andloweralkyl; C is a member selected from the group consisting of halo,loweralkyl, loweralkoxy, trifluoromethyl and dimethylamino; D is halo; Eis loweralkyl; and F is loweralkyl.

Accordingly, this invention provides a process of alleviating muscularpain which comprises systemically administering to a subject with suchpain, such as, for example, which may result from muscular spasm orchronic lower back pain, an aforementioned compound as the activeingredient in a concentration adequate to elicit an effective skeletalmuscle relaxant response. Preferably, dosage unit forms containing fromabout 15 to about 500 mg of such active ingredient are employed formuscular relaxation purposes. A suitable human regimen contemplated forthe preferred compounds disclosed above is 15 to 500 mg orally orparenterally administered three or four times a day.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated, all parts areby weight.

EXAMPLE I 1-m-Chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea

To a suspension of creatinine (5.66 g, 0.05 mole) in 150 ml. of drydimethylformamide (DMF) is added 7.68 g (0.05 mole) ofm-chlorophenylisocyanate. The mixture is stirred for 2 hours and heatedon a steam bath for 30 minutes. During this time the solution becomesclear (yellow). The solution is filtered and the filtrate cooled. Iceand ice-water are added to the filtrate. A light yellow solidprecipitates and is filtered off. After recrystallizations fromacetone-methanol and tetrahydrofuran-ether, the pure product,1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, isobtained, mp 180°-180.5°C.

Analysis: Calcd. for C₁₁ H₁₁ ClN.sub. 4 O₂ : C, 49.54; H, 4.16%. Found:C, 49.45; H, 4.19%.

EXAMPLE II 1-m-Chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea hydrate

About 120 g of pure1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidine)urea obtainedaccording to Example I is dissolved in 400 ml of DMF and poured withvigorous stirring into about 3.5 liters of water. The resultant finecrystals of1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea-hydrateare collected by filtration and washed well with water, dried at roomtemperature for 4 days followed by drying (room temperature) in vacuo at5.0 mm for 8 hr; yield about 120 g; mp 180.5°-181.5°C.

Analysis: Calcd. for C₁₁ H₁₁ ClN.sub. 4 O₂.sup.. H₂ O:C, 46.41; H, 4.60;N, 19.68; H₂ O, 6.33%. Found: C, 46.43; H, 4.62; N, 19.83; H₂ O, 6.37,6.59, 6.41%.

EXAMPLE III1-(2,6-Dichlorophenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea

Following the procedure of Example I, but substituting an equivalentamount of 2,6-dichlorophenylisocyanate for the m-chlorophenylisocyanateused therein,1-(2,6-dichlorophenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea isobtained: m.p. 211°-212°C. dec.

Analysis: Calcd. for C₁₁ H₁₀ Cl₂ N₄ O₂ :C, 43.87; H, 3.35%. Found: C,43.55; H, 3.31%.

EXAMPLE IV 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-methoxyphenylurea

To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 mldry DMF, p-methoxyphenylisocyanate (14.91 g, 0.100 mole) is addeddropwise over a period of about 15 minutes with cooling. After stirringfor 8 hours, the mixture is poured into about 500 ml of ice water toyield white crystals of product which are filtered off, washed withwater and purified by recrystallization (twice) fromtetrahydrofuran-methanol. The crystalline product is reduced to finersize by adding a solution of the product in minimal DMF to vigorouslystirred water (about 1.1 liters) and filtering off the resultantcrystals which are then dried at room temperature in vacuo for 24 hours;m.p. 193°-5°C dec.

EXAMPLE V

Following the procedure of Example IV, but substituting equivalentamounts of an appropriate imidazolidin-4-one and an appropriatearylisocyanate, the following respective products are obtained:

1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-(3,4-dichlorophenyl)ureahemihydrate; m.p. 199°-202°C. dec.;

1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-m-methoxyphenylurea hydrate;m. p. 144°C.; and

1-m-chlorophenyl-3-(4-oxo-2-imidazolidinylidene)urea; m. p. 225°-227°C.dec.

EXAMPLE VI 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-chlorophenylurea

To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 mldry DMF, p-chlorophenylisocyanate (15.36 g, 0.100 mole) is addeddropwise with cooling. The mixture is stirred for 16 hours and thenpoured into about 500 ml of iced-water to yield the crystalline productwhich is filtered off, washed with water and recrystallized twice fromacetone-methanol, once from tetrahydrofuran (THF) and then fromDMF-methanol. The resultant pure1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-chlorophenylurea is driedin vacuo for 24 hours; m.p. 190°-2°C dec.

EXAMPLE VII 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-tolylurea

To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 mldry DMF, p-tolylisocyante (13.31 g - 0.100 mole) is added dropwise overa period of about 15 minutes with cooling. After stirring for 3.5 hrs.,the mixture is poured into about 500 ml iced-water to give whitecrystals of product which are filtered off and washed with water.Recrystallization of the product from acetone-methanol and then fromTHF-methanol affords the product,1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea. The crystallineparticles are reduced in to finer size by adding a solution of thethus-obtained product in minimal DMF to about 1.1 liters of vigorouslystirring water, filtering off and drying the resultant fine crystals invacuo for 24 hours; m.p. 198°-200°C dec.

EXAMPLE VIII

1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-m-tolylurea is obtained byrepeating the procedure of Example VII with an equivalent amount ofm-tolylisocyanate substituted for the p-tolylisocyanate used therein;reaction time is six hours; recrystallization twice from THF-methanol;m.p. 183°-185°C. dec.

EXAMPLE IX

1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-m-trifluoromethyl-phenylureais obtained by repeating the procedure of Example VII with an equivalentamount of m-trifluorophenylisocyanate substituted for thep-tolylisocyanate used therein; reaction time is six hours;recrystallization from acetone-methanol; m.p. 197°-8°C dec.

EXAMPLE X 1-(1-Methyl-4-oxoimidazolidinylidene)-3-(2,6-xylyl) urea

A suspension of 5.66 g (0.05 mole) of creatinine and 7.36 g (0.05 mole)of 2,6-xylylisocyanate in 200 ml of dry THF is heated under refluxovernight (about 15 hours). The hot solution is filtered and thefiltrate diluted with ether to about 400 ml total volume, giving thecrude product. Recrystallization from methanol affords pure1-(1-Methyl-4-oxoimidazolidene)-3-(2,6-xylyl) urea, m.p. <190°C dec.

Analysis: Calcd. for C₁₃ H₁₆ N₄ O₂ (260.30): C, 59.98; H, 6.20%. Found:C, 60.17; H, 6.24%.

EXAMPLE XI 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-phenylurea

The procedure of Example IV is followed except that an equivalent amountof phenylisocyanate is substituted for the p-methoxyphenyl-isocyanateused therein to yield as final product:1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-phenylurea. m.p. (185°)187°-9°C.

EXAMPLE XII

By repeating the procedure of Example VI, except that an equivalentamount of an appropriate 2-imino-1-loweralkylimidazolidin-4-one and anappropriate aryl isocyanate are utilized as reactants, the followingrespective products are obtained:

1-(1-ethyl-4-oxo-2-imidazolidinylidene)-3-phenyl urea;

3-m-bromophenyl-1-(1-methyl-4-oxo-2-imidazolidinylidene) urea, m.p.183°-184°C dec;

3-p-ethoxyphenyl-1-(1-n-octyl-4-oxo-2-imidazolidinylidene) urea;

3-m-ethylphenyl-1-(1-ethyl-4-oxo-2-imidazolidinylidene) urea;

1-(3,4-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea,m.p. 219°-221°C dec;

1-(p-trifluoromethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, m.p. 197°-200°C dec;

1-(p-t-butylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea, m.p.188°-189°C; and

1-(3-n-propylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea, m.p.167°-168°C.

example xiii1-(3-chlorophenyl)-3-(1,3-dimethyl-4-oxo-2-imidazolidinylidene) urea

A mixture of 6.35 g (0.050 mole) of1,3-dimethyl-2-iminoimidazolidin-4-one, 7.85 g (0.050 mole) of3-chlorophenylisocyanate and 75 ml of dry tetrahydrofuran is stirred atroom temperature for 4 hours. The solution is evaporated in vacuo andthe residue is crystallized from acetonitrile. Two recrystallizationsfrom acetonitrile - ether gives pure product,1-(3-chlorophenyl)-3-(1,3-dimethyl-4-oxo-2-imidazolidinylidene)urea,m.p. 134°-137°C.

EXAMPLE XIV1-(3-Chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea.

To a stirring suspension of 7.92 g (0.07 mole) of creatinine in 50 ml ofdry DMF is added 9.08 g (0.05 mole) of 3-chloro-2,6-dimethylphenylisocyanate. After stirring for four hours, the reaction mixture isfiltered through a diatomaceous earth pad to remove unreactedcreatinine. Addition of a large excess of ice water precipitates a gummysemisolid mass which eventually crystallizes. After blowing the productto dry it for about eighteen hours, it is recrystallized fromacetone-ether. Finally the product is taken up in dichloromethane andthe resulting solution is filtered through diatomaceous earth.Concentration and dilution with ether gives pure product,1-(3-chloro-2,6-dimethylphenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea; m.p. 140°-141.5°C.

EXAMPLE XV1-(2,6-dimethylphenyl)-3-(5,5-diphenyl-4-oxo-2-imidazolidinylidene) urea

A suspension of 6.95 g (0.0306 mole) of5,5-diphenyl-2-amino-2-imidazoline-4-one in 300 ml of dry DMF is treatedwith 4.5 g (0.0306 mole) of 2,6-dimethylphenylisocyanate. The reactionmixture is stirred at 40°C for 2 hours. It is then poured into coldwater and the resulting solids are filtered off. To the crude product isadded 30 ml of water with heating; acetone is added to the heated slurryuntil all solids go in solution (1.5 liters of acetone). The solution isthen evaporated to a volume of 300 ml., chilled, and the resultingsolids are filtered off to give1-(2,6-dimethylphenyl)-3-(5,5-diphenyl-4-oxo-2-imidazolidinylidene)urea, the pure product; no m.p. up to 350°C.

Analysis: Calcd. for C₂₄ H₂₂ N₄ O₂ : C, 72.32; H, 5.56%. Found: C,72.00; H, 5.68%.

EXAMPLE XVI1-(1,3-Dimethyl-4-oxo-2-imidazolidinylidene)-3-(2,6-dimethylphenyl)urea.

A mixture of 6.35 g (0.050 mole) of1,3-dimethyl-2-iminoimidazolidin-4-one and 7.25 g (0.050 mole) of2,6-dimethylphenylisocyanate in 75 ml. of dry tetrahydrofuran is stirredat room temperature for two hours followed by refluxing it for thirtyminutes. The reaction mixture is evaporated in vacuo to give a solid,which is crystallized from tetrahydrofuran-ether. Two morerecrystallizations from the same solvent mixture gives pure product,1-(1,3-dimethyl-4-oxo-2-imidazolidinylidene)-3-(2,6-dimethylphenyl)urea; m.p. 115.5°-118.5°C.

EXAMPLE XVII

Following the procedure of Example XVI, but substituting equivalentamounts of an appropriate imidazolidin-4-one and an appropriatearylisocyanate for the 1,3-dimethyl-2-iminoimidazolidin-4-one and2,6-dimethylphenylisocyanate used therein, the following respectiveproducts are obtained:

1-(3-chlorophenyl)-3-(1-octyl-4-oxo-2-imidazolidinylidene) urea, m.p.98°-100°C;

1-(1-octyl-4-oxo-2-imidazolidinylidene)-3-phenylurea, m.p. 109.5°-110°C;

1-(3-chlorophenyl)-3-(1-methyl-4-oxo-5-benzyl-2-imidazolidinylidene)urea,m.p. 167°-168°C; and

1-(1-methyl-4-oxo-5 benzyl-2-imidazolidinylidene)-3-phenylurea, m.p.158°-160°C.

example xviii 1-(methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenylurea.

To a stirred slurry of 12.45 g (0.11 mole) of creatinine in 100 ml ofdry DMF is added 16.41 g (0.1 mole) of m-nitrophenyl isocyanate(previously recrystallized from benzenepentane). After 9 hours, icewater is gradually added until crystallization occurres. A large excessof ice water precipitates the product as gummy crystals which thencrystallize. The crude product is allowed to air dry for several days.Recrystallization from THF-H₂ O followed by THF gives pure product,1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl urea; m.p.182°-188°C sl. dec.

EXAMPLE XIX

Following the procedure of Example XVIII, but substituting an equivalentamount of an appropriate arylisocyanate for the m-nitrophenylisocyanateused therein, the following respective products are obtained:

1-(1-methy-4-oxo-2-imidazolidinylidene)-3-(p-nitrophenyl)urea, m.p.220°-223°C dec; and

1-(p-dimethylaminophenyl)-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea;m.p. 210°-216°C dec.

EXAMPLE XX

Following the procedure of Example X, but substituting equivalentamounts of an appropriate imidazolidin-4-one and an appropriatearylisocyanate for the creatinine and 2,6-xylylisocyanate used therein,the following respective products are obtained:

1-(3-chlorophenyl)-3-(3-methyl-4-oxo-2-imidazolidinylidene) urea; m.p169°-171°C; and

1-(3-chlorophenyl)-3-(5,5-diphenyl-4-oxo-2-imidazolidinylidene)urea;m.p. 274°-277°C.

EXAMPLE XXI

Following the precedure of Example I, but substituting an equivalentamount of 2-imino-1-methyl-hexahydropyrimidin-4-one for the creatinineused therein,1-(1-methyl-4-oxo-2-hexahydropyrimidinylidene)-3-p-chlorophenyl urea isprepared.

EXAMPLE XXII

Following the precedure of Example X, but substituting an equivalentamount of 2-imino-1-methyl-hexahydropyrimidin-4-one for the creatinineused therein,1-(1-methyl-4-oxo-2-hexahydropyrimidinylidene)-3-(2,6-xylyl) urea isprepared.

EXAMPLE XXIII

Following the procedure of Example VI, but substituting equivalentamounts of 2-imino-1-methyl-hexahydropyrimidin-4-one and appropriatearyl isocyanate for the creatinine and p-chlorphenylisocyanate usedtherein, the following are prepared:

1-(1-methyl-4-oxo-2-hexahydropyrimidinylidene)-3-(p-ethoxyphenyl) urea;

1-(1-methyl-4-oxo-2-hexahydropyrimidinylidene)-3-(p-dimethylaminophenyl)urea; and

1-(1-methyl-4-oxo-2-hexahydropyrimidinylidene)-3-(p-nitrophenyl) urea.

The above examples are intended to illustrate, but not to limit, thescope of the present invention, which is defined in the followingclaims.

What is claimed is:
 1. A 4-oxo-2-imidazolidinylidene urea having theformula: ##SPC8##wherein R₁ is a member selected from the groupconsisting of hydrogen and loweralkyl; R₂ is a member selected from thegroup consisting of hydrogen and loweralkyl; R₃ is a member selectedfrom the group consisting of hydrogen, phenyl, nitrophenyl,trifluoromethylphenyl, diloweralkylaminophenyl, and phenyl substitutedwith from one to three members each selected from the group consistingof halo, loweralkyl, and loweralkoxy; R₄ is a member selected from thegroup consisting of hydrogen, phenyl, nitrophenyl,trifluoromethylphenyl, diloweralkylaminophenyl, phenyl substituted withfrom one to three members each selected from the group consisting ofhalo, loweralkyl, and loweralkoxy, and phenylalkyl; and Ar is a memberselected from the group consisting of phenyl, nitrophenyl,trifluoromethylphenyl, diloweralkylaminophenyl, and phenyl substitutedwith from one to three members each selected from the group consistingof halo, loweralkyl, and loweralkoxy; provided that said R₃ and said R₄are other than 2,6-disubstituted phenyl.
 2. A4-oxo-2-imidazolidinylidene urea having the formula: ##SPC9##wherein Aris a member selected from the group consisting of phenyl,loweralkylphenyl, loweralkoxyphenyl, halophenyl, nitrophenyl,trifluoromethylphenyl, diloweralkylaminophenyl, di-loweralkylphenyl anddihalophenyl.
 3. A 4-oxo-2-imidazolidinylidene urea having the formula##SPC10##wherein X is a member selected from the group consisting ofhydrogen, halo, methyl, ethyl, methoxy, ethoxy, and trifluoromethyl. 4.A 4-oxo-2-imidazolidinylidene urea having the formula: ##SPC11##whereinAr is a member selected from the group consisting of ##SPC12## wherein Ais a member selected from the group consisting of halo and loweralkyl; Bis a member selected from the group consisting of halo and loweralkyl; Cis a member selected from the group consisting of halo, loweralkyl,loweralkoxy, trifluoromethyl, and dimethylamino; D is halo; E isloweralkyl; and F is loweralkyl. 5.3-Halophenyl-1(1-methyl-4-oxo-2-imidazolidinylidene) urea. 6.1-m-Bromophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea. 7.1-m-Methoxyphenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea. 8.3-Loweralkylphenyl-1-(1-methyl-4-oxo-2-imidazolidinylidene) urea. 9.1-m-Chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea. 10.1-m-Chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene) urea hydrate.11. 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-methoxyphenyl urea. 12.1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-chlorophenyl urea. 13.1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea. 14.1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-m-tolyl urea. 15.1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-m-trifluoromethylphenyl urea.16. 1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-(2,6-xylyl) urea. 17.1-(1-Methyl-4-oxo-2-imidazolidinylidene)-3-phenyl urea.